Abstract Hypertension (HTN) is a prevalent cardiovascular condition and a leading risk factor for other cardiovascular diseases. Despite advances in prevention and therapy, ~20% of patients are resistant or refractory to current treatments. In most cases, treatment-resistant HTN (HTN) is strongly `neurogenic', being accompanied by exaggerated sympathetic nerve activity (SNA) and linked with renin-angiotensin system (RAS) and immune system activation. If it remains untreated, neurogenic hypertension can lead to numerous comorbidities such as stroke, dementia, diabetes, kidney disease, obstructive sleep apnea, and neurological disorders such as Alzheimer's disease. While studies of neurogenic HTN report inflammation in brain regions that control SNA, specific mechanisms driving hyperactivity of pre-sympathetic neurons have not been identified. Salt-sensitive HTN has been characterized by significant changes in neuronal properties following increased dietary salt intake and, most importantly, prior to blood pressure increase. Our recent work indicates that peripheral and central inflammatory mechanisms lead to molecular alterations in neurons in key autonomic brain regions such as the hypothalamus. More specifically, we found that moderately high salt diet (2%) activates bone marrow (BM)-derived IL17a-expressing CD4+ immune cells (ICs), which alone are capable of increasing blood pressure (BP). This was associated with infiltration of CD4+ ICs and activation of microglia in the paraventricular nucleus (PVN) of the hypothalamus, as well as with specific molecular changes in the PVN that may act as potent sensitizers of sympathetic control neurons, long implicated as drivers of exaggerated SNA in salt-sensitive HTN when challenged by angiotensin II (Ang II). Thus, this model provides several conceptual advantages in elucidation of early mechanisms of neuroinflammation-dependent neurogenic HTN, as we are able to investigate early mechanisms of neuronal changes prior to development of HTN. Our novel hypothesis is focused on the establishment of connection between infiltration of salt-activated IL17a-expressing ICs and exaggerated discharge of PVN pre-sympathetic neurons to Ang II. We postulate that the immune-driven adaptations strongly reflect transcriptional activity driven by nuclear factor kappa B (NF-kB), a major transcriptional factor activated by pro-inflammatory cytokines, including the IL-17a and microglial-derived TNF?. This results in the increase of SNA and promotes establishment of HTN not only through neurogenic vasoconstriction but also by stimulating continued release of BM ICs mediated by ?1/?2 adrenoceptor activation in the BM. Outcomes will inform the future development of novel therapeutics to better manage neurogenic HTN, and potentially will extend to advance the treatment of other salt-exacerbated autoimmune disorders such as colitis, psoriatic arthritis and systemic lupus erythematosus.